Breast cancer is a significant health concern in the United States, representing the second leading cause of cancer death in women. The lethality of breast cancers reflects their acquisition of invasive and metastatic phenotypes, events that account for nearly 90% of the mortality associated with mammary carcinomas. While the 5-year survival rate for women diagnosed with localized disease is high at 98%, this rate drops abruptly to 23% for women who exhibit evidence of metastasis at the time of diagnosis. At present, the molecular mechanisms that underlie the development and initiation of metastasis remain incompletely understood, as does the means to effectively monitor patients for disease progression. Along these lines, breast cancer cells often disseminate in patients with small mammary tumors (<4 mm) and prior to the point where the disease becomes symptomatic. Similarly, disseminated breast cancer cells often escape clinical detection by acquiring dormant phenotypes, only to reemerge later as aggressive recurrent tumors that no longer respond to the therapeutic regimens used in treating the original tumor.
Breast cancer is not a homogenous disease, but is instead a heterogeneous disease comprised of at least 5 genetically distinct subtypes that exhibit disparate (i) histopathological features, grades, and markers; (ii) clinical presentations, prognoses, and outcomes; and (iii) responses to chemotherapies. Collectively, these challenges highlight the need to develop novel diagnostic platforms capable of detecting breast cancers in otherwise seemingly healthy women.
Amongst individual breast cancer subtypes, those classified as triple-negative breast cancers (TNBCs) are especially lethal due to their highly aggressive and metastatic behavior, and to their propensity to recur following apparent remission. TNBCs lacked expression of hormone receptors (estrogen and progesterone) and ErbB2/HER2. However, they typically possess BRCA1- and p53-defects and/or -deficiencies. This unique phenotype prevented the development of targeted chemotherapies effectively against TNBCs, which also possess a heightened propensity to acquire resistance to standard-of-care chemotherapeutic agents (e.g., doxorubicin, cisplatin, and taxanes). Moreover, the diagnosis of TNBC is one of exclusion, not one of inclusion because specific biomarkers for this disease did not exist. Recently, several serum biomarkers for breast cancer were employed in clinical settings. This limited list included the cancer antigens (CA): CA15-3, CA27.29, and carcinoembryonic antigen (CEA), and all lacked the needed sensitivity and specificity.
Recent findings linked the aberrant expression of LOXL2 to breast cancer metastasis and disease progression, particularly in patients harboring late-stage and poorly differentiated TNBCs (Peinado, H.; Portillo, F.; Cano, A. Switching On-Off Snail: LOXL2 Versus GSK3? Cell Cycle 4, 1749 (2005); Peinado, H. et al., Lysyl Oxidase-Like 2 as a New Poor Prognosis Marker of Squamous Cell Carcinomas. Cancer Research 68, 4541 (Jun. 15, 2008, 2008); Kagan, H. M.; Li, W. Lysyl oxidase: Properties, specificity, and biological roles inside and outside of the cell. Journal of Cellular Biochemistry 88, 660 (2003); and Lucero, H. A.; Kagan, H. M. Lysyl oxidase: an oxidative enzyme and effector of cell function. Cell Mol Life Sci 63, 2304 (October, 2006)). Similarly, dysregulated LOXL2 expression predicts for disease recurrence and poor prognosis in breast cancer patients (Erler, J. T.; Giaccia, A. J. Lysyl oxidase mediates hypoxic control of metastasis. Cancer Res 66, 10238 (Nov. 1, 2006); Payne, S. L.; Hendrix, M. J.; Kirschmann, D. A. Paradoxical roles for lysyl oxidases in cancer—a prospect. J Cell Biochem 101, 1338 (Aug. 15, 2007); Nishioka, T.; Eustace, A.; West, C. Lysyl oxidase: from basic science to future cancer treatment. Cell Struct Funct 37, 75 (2012); Taylor, M. A. Amin, J.; Kirschmann, D. A.; Schiemann, W. P. Lysyl oxidase contributes to mechanotransduction J-mediated regulation of transforming growth factor-β signaling in breast cancer cells. Neoplasia 13, 406 (2011) and Barker, H. E.; Erler, J. E. The potential for LOXL2 as a target for future cancer treatment. Future Oncol 7, 707 (June, 2011).).